Parkash et al. BMC Gastroenterology 2010, 10:43http://www.biomedcentral.com/1471-230X/10/43

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Research articleSeverity of acute hepatitis and its outcome in patients with dengue fever in a tertiary care hospital Karachi, Pakistan (South Asia)Om Parkash*†1, Aysha Almas†2, SM Wasim Jafri†1, Saeed Hamid†1, Jaweed Akhtar†2 and Hasnain Alishah†1

AbstractBackground: Liver injury due to dengue viral infection is not uncommon. Acute liver injury is a severe complicating factor in dengue, predisposing to life-threatening hemorrhage, Disseminated Intravascular Coagulation (DIC) and encephalopathy. Therefore we sought to determine the frequency of hepatitis in dengue infection and to compare the outcome (length of stay, in hospital mortality, complications) between patients of Dengue who have mild/moderate (ALT 23-300 IU/L) v/s severe acute hepatitis (ALT > 300 IU/L).

Methods: A Cohort study of inpatients with dengue viral infection done at Aga Khan University Hospital Karachi. All patients (≥ 14 yrs age) admitted with diagnosis of Dengue Fever (DF), Dengue Hemorrhagic Fever (DHF) or Dengue Shock Syndrome (DSS) were included. Chi square test was used to compare categorical variables and fischer exact test where applicable. Survival analysis (Cox regression and log rank) for primary outcome was done. Student t test was used to compare continuous variables. A p value of less than or equal to 0.05 was taken as significant.

Results: Six hundred and ninety nine patients were enrolled, including 87% (605) patients with DF and 13% (94) patients with DHF or DSS. Liver functions tests showed median ALT of 88.50 IU/L; IQR 43.25-188 IU/L, median AST of 174 IU/L; IQR 87-371.5 IU/L and median T.Bil of 0.8 mg/dl; IQR 0.6-1.3 mg/dl. Seventy one percent (496) had mild to moderate hepatitis and 15% (103) had severe hepatitis. Mean length of stay (LOS) in patients with mild/moderate hepatitis was 3.63 days v.s 4.3 days in those with severe hepatitis (P value 0.002). Overall mortality was 33.3% (n = 6) in mild/moderate hepatitis vs 66.7% (n = 12) in severe hepatitis group (p value < 0.001). Cox regression analysis also showed significantly higher mortality in severe hepatitis group (H.R (4.91; 95% CI 1.74-13.87 and P value 0.003) and in DHF/DSS (5.43; CI 1.86-15.84 and P value 0.002). There was a significant difference for the complications like Bleeding (P value < 0.001), Acute Renal failure (ARF) (P value 0.002), Acalculus cholecystitis (P value 0.04) and encephalopathy (P value 0.02) in mild/moderate and Severe hepatitis groups respectively.

Conclusion: Severe hepatitis (SGPT>300IU) in Dengue is associated with prolonged LOS, mortality, bleeding and RF.

BackgroundDengue fever is an arboviral infection transmitted byAedes ageptyi as well as Aedes Albopictus and causes 4spectra of illness which are an asymptomatic phase, acutefebrile illness, classic Dengue fever (DF), Dengue Hemor-rhagic Fever (DHF) which includes Dengue Shock Syn-drome (DSS) [1-3]. Dengue viral infection has beenrecognized as one of the world's biggest emerging epi-

demic. Throughout the tropics this infection has anannual incidence of 100 million cases of DF with another250,000 cases of DHF and mortality rate of 24,000-25,000per year[1,4,5]. Most of these cases are reported fromSouth East Asian areas which are most favorite tourist'spoint[4,6]. In Pakistan at least two confirmed outbreakshave been reported first in 1994 and second in 2005.Since then we are continuously facing the problem of anepidemic each year in Karachi and some other areas ofPakistan [7,8]. During the last couple of years Pakistanhas become an endemic region as this virus is beingtransmitted westward from India[7].

* Correspondence: om.parkash@aku.edu1 Section of Gastroenterology, Department of Medicine Aga Khan University Hospital Karachi, Pakistan† Contributed equallyFull list of author information is available at the end of the article

BioMed Central© 2010 Parkash et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.

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Dengue fever indicates a bad outcome including deathwhen liver and nervous system are involved simultane-ously by dengue[9]. Atypical manifestations include liverinvolvement, central nervous involvement (encephalopa-thy) and cardiac alterations in DF. None of the studieshave reported about the severity of liver involvement inDengue fever with reference to mortality and Length ofStay (LOS). Liver involvement in dengue fever is mani-fested by the elevation of transaminases representingreactive hepatitis. This has been recognized over the lasttwo decades during the recent epidemics in Brazil[10]. Astudy from Thialand (Retrospective review) has reported34.6% liver dysfunction in pediatric population infectedwith dengue[11]. Elevated transaminases in DF are due tomany conditions like use of hepatotoxic drugs and directattack of virus itself causing these unusual clinical mani-festations. These in turn lead to more serious fate amongthe dengue patients [10,12].

The involvement of liver in dengue fever is not uncom-mon as reported in literature since 1970[13]. In the LiverFunction Tests (LFT) most common abnormality seen iselevated transaminases which are involved in amino acidmetabolism. In approximately 90% of the patients withDF, Aspartate Aminotransferase (AST) is higher than theAlanine Aminotransferase (ALT) [14,15]. DF initiates theinflammatory responses leading to liver parenchymalchanges and causing release of transaminases in circula-tion[16]. Since DF is an emerging infection in Pakistanand very little is known about the severity of hepatitis andtheir outcome in patients with dengue fever when liver isinvolved. Therefore we aim to assess the frequency ofhepatitis in dengue infection. We also aim to comparetheir outcome (mortality, length of stay and complica-tions) between patients with mild to moderate and severehepatitis in dengue infection.

MethodsWe conducted a cohort study on inpatients with denguefever at Aga Khan University Hospital Karachi Pakistan(AKUH). All patients were uniformly tested on day ofadmission using a standardized protocols being used inhospital for patients with dengue infection. We selected acohort of patients with hepatitis from these patients withdengue infection. AKUH is part of Aga Khan Develop-ment Network aimed at providing high quality of healthcare, teaching and research. This University Hospital has542 beds in operation and provides services to over38,000 hospitalized patients and to over 500,000 outpa-tients annually with the help of professional staff andfacilities that are among the best in the region.

Ethical clearance was taken from the institutional Ethi-cal Review Committee (ERC). All inpatients of age ≥ 14years who had history of acute fever, positive dengue IgMand whose ALT were done, were included in the study.

We had excluded all those patients who had underlyingChronic Liver Disease (CLD) or known positive serologyfor viral hepatitis (HBsAg or HCVAb; n = 6) and thosepatients who had malaria.

We divided this cohort of dengue inpatients with hepa-titis into two groups based on ALT level; Mild (upto 5times normal) to Moderate (5- 10 times) acute hepatitis:ALT 23-300 IU/L, severe acute hepatitis: ALT > 300 IU/Lor ≥ 10 times [10,17-21]. Primary outcome measureswere mortality and LOS. Secondary outcome measureswere different complications; defined as; a) Bleeding wasdefined as either mucosal bleeding (epistaxis or gumbleed) or Gastrointestinal (GI) bleed; b). Acute RenalFailure (ARF) was defined as rise of creatinine (Cr) >3times of normal [22]; c) Encephalopathy was defined asaltered mental status (drowsiness, lethargy, agitation, orcoma) for ≥ 8 hours [23]; d) Shock was defined as systolicpressure < 90 mm Hg [24]; e) Acalculous cholecystitiswas defined as inflammation of gall bladder withoutstone on ultrasound[2]. We also dichotomized the databased on diagnosis into DF and DHF/DSS for the primaryoutcome measures (mortality and LOS) [25].

We required a minimum sample size of 350 patients byassuming 35% prevalence of liver dysfunction in patientswith dengue fever, with 0.05 bound on error(precision)and 95% confidence level[11].

Data was collected on predesigned proforma whichincluded demographics, clinical presentation, laboratoryparameters and outcome (in hospital mortality, length ofstay and complications). We included all patients who ful-filled inclusion criteria and were admitted in the medicalward through emergency room or clinic. Informed con-sent was taken from patients. Proforma was filled foreach patient. Each patient was categorized either intomild to moderate or severe hepatitis groups based onALT levels and these patients were followed for their out-come till the end of inpatient stay.

Statistical analysisStatistical Package for Social Sciences (SPSS) version 16was used for analysis. Results are presented as mean ±standard deviation (SD) for continuous variables, fre-quency and percentage are given for qualitative variables.For non normally distributed quantitative variablesmedian and Inter Quartile Ranges (IQR) were used. Chisquare test was used to compare categorical variables andfischer exact test were used when numbers were toosmall to perform the chi-square testing. Student t test wasused to compare continuous variables. In survival analy-sis cox proportion hazard ratio (Cox regression) wasdetermined for mortality in DHF/DSS and severe hepati-tis after fulfilling the assumption of proportional hazardratio. Kaplan Meir plot of survival over time and log ranktest were also used. A p value of ≤ 0.05 was taken as sig-

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nificant. Death rates for 10 days in each category werecalculated and 95% CI for death rate ratio were also cal-culated.

ResultsTotal of 699 patients with DF were included, among them65% were male. Mean age of patients was 31.87 ± 13.55years. Approximately 86% (n = 604) were admitted withDF, 12% were admitted with DHF and only 2% had DSS.Malarial parasite was negative in all patients. Mean dura-tion of fever was 6 ± 3.27 days with mean temperature of38.5 ± 1°C. Among clinical features, 48.6% had nausea/vomiting, 18.2% had abdominal pain, 17% had rash, 16%had body ache, 10% had diarrhea, 9% had cough, 5.4% hadhematemesis, 5.2% had bleeding gum,4.3% hadmalena,4% had altered mental status and 3.1% had jaun-dice. On abdominal examination, 7% had right hypo-chondric tenderness and 1.4% had epigastric tenderness.In hemodynamics, mean pulse was 96 ± 18.5 beats/min,mean systolic blood pressure was 113 ± 16 mmHg withmean diastolic blood pressure of 71 ± 11 mmHg. Thecomplete blood count showed mean hemoglobin of 13.71± 2.37 gm/l, mean hematocrit of 40.07 ± 6.8%, meanwhite blood cell count of 5.5 ± 5/cmm and median plate-let count of 48/cmm;IQR 23-96/cmm. Mean ActivatedPartial Thromboplastin Time (APTT) was 36.34 ± 11.56seconds with control of 40 seconds. Mean Cr was 1.12 ± 1mg/dl. Liver function tests (LFTs) show the median ALTof 88.50 IU/L; IQR 43.25-188 IU/L, median AST of 174IU/L; IQR 87-371.5 IU/L, median ALK.Phos 80 IU/L;IQR 54-129 IU/L and median T.Bil of 0.8 mg/dl; IQR 0.6-1.3 mg/dl. Almost 86% (599) of the patients had elevatedALT (hepatitis). The mean LOS was 3.88 ± 2.7 days in thispopulation. Mortality was 2.7% in our study. Amongcomplications, we have found 1.7% bleeding, 1.3% shock,2.7% ARF 3.9% acalculous cholecystitis and 2.9% enceph-alopathy.

Severe hepatitis was present in 15% and mild to moder-ate hepatitis in 71% while 14% had normal ALT. Patients

with normal ALT were excluded from further analysis.Overall mortality (n = 18) was significantly higher insevere hepatitis group (66.70%;n = 12) as compared tomild to moderate hepatitis (33.30%;n = 6). The survivalprobability of mild to moderate and severe hepatitisgroup according to Kaplan-Meir curve is shown figure 1with numbers at risk below the figure. Differences inoverall survival between these two groups is significant (Pvalue < 0.005; log rank). Mean length of stay in patientswith mild/moderate hepatitis was 3.63 days versus 4.3days in those with severe hepatitis (figure 2). Cox regres-sion (survival analysis) also showed the significantlyhigher mortality in severe hepatitis group (H.R 4.91; 95%CI 1.74-13.87 and P value 0.003) and DHF/DSS group(H.R 5.43; CI 1.86-15.84 and P value 0.002) with referenceto mild to moderate hepatitis and DF respectively. Sub-group analysis of DF and DHF/DSS for mortality hasshown significantly higher mortality in severe hepatitisgroup versus mild to moderate hepatitis (3/436 versus 3/81, P value 0.04 in DF; 3/60 versus 9/22, p value < 0.001 inDHF/DSS group respectively). Comparison of subgroupsDF and DHF/DSS with reference to outcome is shown intable 1. Comparison of secondary outcome measures isshown in table 2.

DiscussionWe report the largest cohort study from south Asia (Paki-stan) on hepatitis in dengue fever patients and their asso-ciation with outcome. Currently dengue is perhaps themost common rapidly emerging viral infection through-out the world and Pakistan reported its first outbreak in1994[26].

Deranged liver functions are common in patients withdengue infection due to direct attack on liver cells orunregulated host immune response against the virus [19].Hence measurement of AST and ALT are mandatory tosee the liver involvement [10]. We have found in ourstudy that deranged liver functions are an important fea-ture in patients with dengue infection. Almost 86% of the

Table 1: Primary outcome measures according to severity of hepatitis within two categories diagnosis

Diagnosis Categories Severity of hepatitis Deaths n Death rate (Deaths/10 day)

H.R (95% CI; UCI, LCI)^

P value(Difference in death rate)!

LOS ± SD P value

Dengue fever (n = 517) Mild to Moderate Hepatitis (n = 436)

3 0.019 2.97(0.48,18.6) 0.283 3.50 ± 1.54 <0.025

Severe hepatitis (n = 81) 3 0.093 3.96 ± 2.27

DHF/DSS(n = 82)

Mild to Moderate Hepatitis (n = 60)

3 0.010 5(1.3,16) 0.003 4.60 ± 2.87 .212

Severe hepatitis (n = 22) 9 0.073 5.60 ± 3.85

^H.R = Hazard Ratio, UCI = Upper confidence interval, LCI = Lower confidence interval! Log Rank value

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patients in our study had hepatitis (elevated ALT) and95% patients had elevated AST. However Wong et alreported that AST abnormality was predominantlyhigher as compared to ALT; 91% and 72% respectively,which is consistent with our study. However we reporthigher values of AST and ALT in our study populationthan reported by Wong et al and other studies[10,19,27,28]. Souza et al also reported the similar trendof AST/ALT in dengue fever but with much lower level ascompared to our population[10]. This difference can beexplained on the basis that in our study all patients were

inpatients while in their study all the patients were outpa-tients with less severe disease. Furthermore a study fromAsia pacific region (Taiwan) by Kuo et al has shownapproximately 90% of the AST abnormality in denguepatients which is consistent with our study[29]. We canassume that reasons for higher ALT or AST levels in ourpopulation are either due to more virulent strain of den-gue infection or virus is more hepatotoxic. Therefore fur-ther studies are required to highlight the possiblehepatotropic nature of this virus as well as virulence andtype of virus.

Immune responses including the innate and acquired;play important role in determining the response to anyvirus. Causation of the severity dengue infection has beenexplained by the hypothesis of immune enhancement andvirulence nature of virus [21]. Chaturvedi et al in theirstudy detected the appearance of different helper cellscytokines in human white blood cells cultures infected invitro with dengue virus type 2. In their study they havereported that during dengue infection; monocytes, Bcells, T cells and mast cells produce large amounts ofcytokines [30]. Based on this we can hypothesize the sim-ilar mechanism responsible for hepatoxicity in our studypopulation. Despite all this, role of host immunity in den-gue infection is still very unclear. Dengue antigens havebeen identified within the liver parenchyma on postmor-tem of these patients hence virus seems to be able to rep-licate within the hepatocytes. Unregulated host immuneresponse may play some part in severity of dengue infec-tion therefore by modifying the immune response, severeinfection can be prevented [21].

We have seen significantly higher mortality in patientswith severe hepatitis. We report 2.7% mortality in ourstudy population. Similar mortality figure (2.6%)wasreported in an earlier study from Pakistan but with asmaller sample size (n = 225)[31]. Literature regarding

Table 2: Complications in two groups of severity of hepatitis

Complications Mild to moderate (n = 496) Severe hepatitis (n = 103) P value

Bleeding1 (n) 3 7 <0.0016

Renal failure2 (n) 8 8 0.002

Encephalopathy3 (n) 7 11 0.02

Shock4 (n) 6 2 0.406

Acalculus cholecystitis5 (n) 14 7 0.04

1. Either mucosal bleeding (epistaxis or gum bleed) or Gastrointestinal (GI) bleed2. Acute Renal Failure (ARF) was defined as rise of creatinie >3 times(13)3. Encephalopathy was defined as altered mental status for > 8 hours (drowsiness, lethargy, agitation, or coma)(19)4. Shock was defined as Hypotension (defined as systolic pressure < 90 mm Hg)(14)5. Acalculus cholecystitis was defined as inflammation of gall bladder without stone on US (15)6. Anayzed by fischer exact test

Figure 1 Kaplan-Meir curve of survival over time in two groups of patients with hepatitis.

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the mortality in dengue infection with impaired liverfunction is scarce. Nguyen TL et al concluded in theirstudy on 45 patients in Vietnam, that DHF may causemild to moderate liver dysfunction in most cases; onlysome patients may suffer from acute liver failure leadingto encephalopathy and death [9]. However liver involve-ment was not studied with reference to mortality. Shahhas reported high mortality in dengue patients with hep-

atitis and encephalopathy[32]. However this was a smallstudy from India, done on 4 pediatric patients only. Ourstudy is the first large study from South Asia region, tohighlight the mortality with deranged liver function indengue patients. The self limiting clinical course of den-gue infection can be prolonged when the liver is involvedas suggested by Souza et al[10]. Hence we have seenworse prognosis in terms of mortality and length of stay

Figure 2 Box plot showing length of stay (in days) in two groups of severity of hepatitis.

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in our study patients when there is a severe hepaticinvolvement. On further subgroup analysis we also sawthat mortality was significantly higher in severe categoryof hepatitis in both DF and DSS. We can postulate thatsevere hepatitis may be a significant contributing factorto mortality in patients with dengue infection. Howeverfurther immunologic studies need to be done to establishthe cause of liver involvement; whether it is due to virusitself or due to immunologic reaction (reactive hepatitis).

The mean length of stay was approximately 4 days inour study population with dengue infection while a studyfrom Singapore by Lye et al[33] had reported mean LOSof 3 days. Khan et al reported in their study (166 patients)in Saudi population; that median duration of hospital staywas 4 days in dengue patients but there was no compari-son based on liver functions [34]. No study has reportedLOS in comparison with liver involvement as yet. Severehepatitis in dengue fever does affect the LOS when thedisease is mild (DF) but as disease become more severe,severe hepatitis does not affect the LOS.

We have found that clinical complications like bleeding,renal failure, encephalopathy and Acalculous cholecysti-tis were higher in those who had severe hepatitis. A studyfrom Saudi population by Khan et al had made an associ-ation between high AST level with these complica-tion[34]. But we have seen the complications withreference to hepatitis based on serum ALT levels. Wehave seen significantly higher bleeding complication inpatients with severe hepatitis. Similarly Kuo CH et al hasreported higher bleeding episodes in those who had highlevels of AST, ALT and GGT[29]. An other study has alsoreported significantly higher spontaneous bleeding epi-sodes in patients with elevated ALT and Alk.Phos [27].Nguyen TL et al has also found significantly higher eleva-tion of AST and ALT in DHF patients with gastrointesti-nal haemorrhage [9]. We can postulate that derangedliver functions may have a significant role in bleeding inaddition to thrombocytopenia. We have found signifi-cantly higher proportion of patients with renal failurewho had severe hepatitis. There are case reports of acuterenal failure/injury in dengue fever in the literature, butnone of them have been studied along with liver involve-ment in adults[35]. Encephalopathy in our study popula-tion was also significantly higher in the severe hepatitisgroup. There are case reports available regarding theencephalopathy in dengue infection in adult popula-tion[36]. However encephalopathy is well studied in pedi-atric population[37]. Acalculous cholecystitis wassignificantly high in the patients with severe hepatitis.Acalculous cholecystitis is very known entity amongpatients with dengue fever but none of them have showncomparison according to severity of hepatitis[38,39].

Three percent of the patients had jaundice in our studypopulation. Larreal Y et al has reported jaundice in only 2

out of 63 patients in their study on hepatic alteration indengue fever [40].

Strength and LimitationsThis is the largest study from South Asia on patients withdengue fever. This is the first study which is comparingthe outcome in dengue patients with hepatitis.

This study has limited external validity since this isstudy of inpatients and has not included patients whohave visited outpatient and other hospitals in the city.The study population in our tertiary care hospital is frommiddle to high income population which comprises onlysmall percentage of city population. We also did notcheck for the type of dengue virus.

ConclusionWe conclude that majority of the patients with dengueinfection have hepatitis. Severe hepatitis in dengue infec-tion has got worse outcome in terms of length of stay,mortality and complications as compared to mild tomoderate hepatitis. Therefore severe hepatitis can beconsidered as a bad prognostic indicator of outcome indengue infection. Though majority of the patients hadself resolving course of illness but they can be potentialcandidate for acute fulminant hepatic failure. Denguefever should be considered when liver functions arederanged apart from routine hepatotropic viruses. Fur-ther studies are required to establish the fact whetherliver injury is due to hepatotropic nature of the virus ordue to immunologic injury.

New to knowledgeOutcome of dengue fever when there is an involvement ofabnormal liver functions.

List of abbreviationsALT: (Alanine aminotransferase); AST: (Aspartate amin-otransferase); GGT: (Gamma glutamine transferase);Alk.Phos: (alkaline phosphate); IU: (International units);DHF: (Dengue hemorrhagic fever); DF: (Dengue fever).

Authors Information1. Dr Om Parkash (OP); MBBS, FCPS (Medicine)Resident Gastroenterology, Section of gastroenterol-ogy Department of Medicine Student of Masters' inclinical research Aga Khan University Hospital Kara-chi.2. Dr Aysha Almas (AA); MBBS, FCPS (Medicine),MSc in Clinical ResearchSenior Instructor, Section of internal MedicineDepartment of Medicine3. Professor S.M Wasim Jafri (WJ); MBBS, FRCP,FRCPE

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Gastroenterologist and hepatologist, Department ofMedicine4. Professor Saeed Hamid; MBBS, FRCPGastroenterologist and hepatologist, Department ofMedicine5. Professor Javeed Akhtar; MBBS, FRCPProfessor of Medicine and section head of InternalMedicine.6. Professor Syed Hasnain Alishah (HAS); MBBS,FRCPGastroenterologist and HepatologistHead Section Gastroenterology, Department of Med-icine

Competing interestsThe authors declare that they have no competing interests.

Authors' contributionsOP has made the protocol and overall plan of the study. OP has written thefinal manuscript. AA had reviewed the manuscript first draft and helped in revi-sion of article based on reviewers comments each time. AA also helped incoordinating this study. HAS has been the great supervisor who reviewed theprotocol and had given important suggestions during study as well as in revi-sions. WJ has given the moral support. All other authors have reviewed andhelped in drafting the manuscript.

AcknowledgementsMs Fatima Almas has helped in data management and Ms Jai Shree helped in statistical analysis.

Author Details1Section of Gastroenterology, Department of Medicine Aga Khan University Hospital Karachi, Pakistan and 2Section of Internal Medicine, Department of Medicine Aga Khan University Hospital Karachi, Pakistan

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Received: 10 April 2009 Accepted: 7 May 2010 Published: 7 May 2010This article is available from: http://www.biomedcentral.com/1471-230X/10/43© 2010 Parkash et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.BMC Gastroenterology 2010, 10:43

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doi: 10.1186/1471-230X-10-43Cite this article as: Parkash et al., Severity of acute hepatitis and its outcome in patients with dengue fever in a tertiary care hospital Karachi, Pakistan (South Asia) BMC Gastroenterology 2010, 10:43